Adiponectin and chronic kidney disease; a review on recent findings.

Adiponectin is a multifunctional cytokine that has a role in regulating inflammation. In patients without chronic renal failure (CRF) and type 2 diabetics, decreased adiponectin levels are associated with insulin resistance. Lower serum plasma adiponectin values are link to larger tumor size and metastasis in clear-cell carcinoma of the kidney too. However, in patients with established chronic kidney disease (CKD), adiponectin levels are elevated and positively predict progression of disease. In addition, increased levels of serum adiponectin of hemodialysis patients were associated with decrease in bone mineral density in hemodialysis patients. Thus, depending on type of renal failure should be adjusted the adiponectin levels in patients. In CKD patients without diabetic, decreasing adiponectin levels by ARB drugs may be appropriate for inhibition of disease progression.


Clinical implications
Ho et al (11) reported that uremic patients had one-third of the levels of adiponectin (P < 0.001) in compared with nonuremic patients, while females had a 1.5-fold higher levels of adiponectin. Plasma adiponectin level was significantly higher in CKD patients than control group (P < 0.05) and in CKD patients plasma adiponectin inversely correlated with glomerular filtration rate (GFR) (r = -0.570, P < 0.001) (12) and creatinine (r = -0.423; P < 0.01) (13). Another study showed that adiponectin correlated inversely with GFR (r = -0.45; P < 0.001), body mass index (BMI) (r = -0.33; P < 0.01), and visceral fat (r = -0.49; P < 0.001), while a positive association with amount of proteinuria was detected (r = 0.21; P < 0.05) (14). The mean adiponectin levels in the pre-dialysis groups were significantly lower than in the chronic ambulatory peritoneal dialysis (CAPD) group (P < 0.05). The levels of adiponectin were increased for all patients with chronic renal failure (CRF) (15). For patients with normal range GFR and type 2 diabetes, albuminuria inversely correlated with plasma adiponectin (r = −0.31, P < 0.05) (16), while plasma adiponectin positively correlates to intercellular leukocyte adhesion molecule (17). Therefore, adiponectin is associated with parameters of kidney function at the stage of apparently normal kidney function in type 2 diabetes (16). Lenghel et al (17) concluded that median adiponectin was not significantly different in diabetic and non-diabetic subjects, however, the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher adiponectin was independently associated with lower eGFR and higher urinary albumin levels (17). Markedly elevated plasma adiponectin serum values were observed in CKD patients (18,19). In hemodialysis patients, the plasma levels of HMW adiponectin were significantly higher than CKD patients (20). In hemodialysis patients, adiponectin is an indicator for high-density lipoprotein cholesterol (HDL-C) and total-cholesterol levels and is twice its values in these patients (21). Multivariate analysis for kidney transplant recipient patients showed that the presence of metabolic syndrome early after transplantation was independently associated with decreased plasma values of adiponectin (β: -6.39, r (2) 0.195, P < 0.0001) and increased risk for clinical events (OR: 5.6, 95% CI: 1.9, 16.5; P < 0.01) (22). Taherimahmoudi et al (23), described that adiponectin levels were remarkably higher in the patient group before transplantation when compared with healthy subjects (P < 0.001) and after transplantation this level remained significantly higher (P < 0.001). In post-transplant south Asian patients the level of total and HMW adiponectin are lower and may be a novel marker for cardiovascular risk factor (24). Okuno et al (25), demonstrated that in hemodialysis patients increased levels of serum adiponectin were related with decreases in bone mineral density. Therefore adiponectin may has participation in bone resorption especially in end-stage renal disease (ESRD) patients (25). Other changes in adiponectin level include decreased level in clear-cell carcinoma of the kidney depend on tumor size and metastasis (26), and in carotid arteriosclerosis (27). However, there is no significant relationship between adiponectin level and all-cause mortality and cardiovascular death (28). Zoccali et al (29), emphasized that low plasma level of adiponectin and high level of norepinephrine contributing to reverse cardiovascular events in nondiabetic hemodialysis (HD) patients. In patients with CKD changes in HMW-adiponectin was significantly correlated with changes in eGFR (r = 0.597, P = 0.001) (30). In another investigation, although 60% of subjects with CKD have CAD, plasma levels of adiponectin were not decreased in subjects with CRF compared with controls (17.02 ± 9.8 versus 16.40 ± 9.0; P = 0.78). Urinary adiponectin levels, associates inversely with GFR (r = −0.4; P < 0.05) and plasma adiponectin levels (r = 0.9; P < 0.001) (31). In hypertensive stage III-IV CKD individuals, no alterations in inflammatory markers, total or HMW adiponectin was detected (32). In individuals with CAD, metabolic syndrome is related to a lower serum HMW adiponectin, while the presence of CKD is associated with increasing of the serum HMW adiponectin (33). In obesity, CKD at early stages develops in parallel with atherosclerotic process of the carotid arteries, which correlates with attenuation of organ-protecting properties of adiponectin (34). To found the effect of losartan of the level of adiponectin, we recently conducted a randomized double blind clinical trial investigation, on a group of nondiabetic individuals, who were on routine hemodialysis program. In our study, exclusion criteria were presence of chronic active or infections, taking angiotensin converting enzyme or renin-angiotensin system blockers or presence of diabetes. Individuals were allocated into two groups. First group was received losartan 12.5 mg twice in a day for the first week, then 25 mg twice/day during the second week and finally, they received 75 mg/day (50 mg in morning, 25 mg for evening) from the third week to the end of 16th week. Hemodialysis subjects of the second group received placebo. Our patients consisted of 73 nondiabetic hemodialysis participants (females = 33) enrolled to the study. The range of subjects' age was from 13 to 91 years. In our investigation, the mean (±SD) of serum adiponectin value in all subjects was 10.6 (±3.9) µg/ml. In our study, a significant reduction of serum adiponectin serum value after 4 months of treatment by losartan (8.86±3.43 of interventional group versus 10.71 ± 3.94 control group; P < 0.05) was detected. Interestingly, none of the patients had serum potassium value >5 mg/dl or episode of hypotension during our study. In this study, we concluded that, the diminution in serum adiponectin value in non-diabetic patients on routine hemodialysis by losartan might offer potential protection in these groups of patients. However,

Study Population Finding
Sedighi and Abediankenari (12) 42 CKD patients and 46 healthy persons Plasma adiponectin level was significantly higher in CKD patients than control group (P < 0.05) and inversely correlated with GFR (r = -0.570, P < 0.001).
Kir et al (15) 37 patients with CKD on conservative treatment, 34 PD on CAPD, 35 HD and CAPD, and 25 healthy volunteers The mean adiponectin levels in the predialysis groups were significantly lower than in the CAPD group (P < 0.05). The levels of adiponectin was increased for all patients with CRF. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher adiponectin was independently associated with lower eGFR and higher urinary albumin levels.
Shoji et al (38) 103 patients with ESRD undergoing HD and 166 healthy subjects Plasma adiponectin correlated negatively with plasma TG and positively with HDL-C in both healthy and ESRD groups.
Elshamaa et al (18) 78 advanced CKD (stages 4 and 5) pediatric patients undergoing maintenance HD or CT Markedly (P < 0.01) elevated plasma adiponectin levels were detected in CKD patients, especially CT patients, compared to control subjects.

HD patients and 30 patients with CKD
Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with visceral fat area and serum TG and positively associated with plasma total adiponectin.

Ribeiro et al (21) 187 HD patients and 25 healthy
Adiponectin almost doubled its values in patients and seems to be an important determinant in HDL-C and total cholesterol levels, improving the lipid profile in these patients.
Roubicek et al (19) 15 women with ESRD and 17 healthy women Serum concentrations of adiponectin was significantly higher in the ESRD versus control group.
Kaynar et al (39) 150 patients, without active infections or chronic inflammatory conditions Adiponectin and resistin levels in predialysis, peritoneal dialysis and hemodialysis patients were significantly higher than control group (P < 0.001). This study had given significant positive correlations between presence of PEW and serum adiponectin levels (r = 0.349, P < 0.001). High serum resistin and adiponectin levels might have a role in development of PEW among dialysis patients.

Campbell et al (32) 20 hypertensive stage III-IV CKD patients
There was no change in inflammatory markers, total or HMW adiponectin.

Landau et al (40) 2418 individuals without reported diabetes at baseline
Adiponectin was associated with IR in those without CKD but not in those with CKD. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD.
Fonseca et al (41) 40 consecutive adult patients with ESRD who were undergoing kidney transplantation Kidney graft function is an independent determinant of leptin levels, but not of adiponectin.
Alam et al (42) 987 prevalent KTR on all-cause mortality and death-censored graft failure Elevated adiponectin levels are associated with higher risk for death but not allograft failure in prevalent KTR.

Heidari M et al
Taherimahmoudi et al (23) 67 candidates with ESRD along with 30 healthy unrelated donors Adiponectin levels were remarkably higher in the patient group before transplantation when compared with healthy subjects (P < 0.001) and remained significantly higher thereafter (P < 0.001). the mechanism liable for this reduction remains to be investigated (35).

Conclusion
Adiponectin is a multifunctional cytokine which has a role in regulating inflammation. In patients without CKD such as type 2 diabetics, decreased adiponectin levels are associated with insulin resistance. Lower plasma adiponectin levels are associated with larger tumor size and metastasis in clear-cell carcinoma of the kidney. However, in patients with established CKD, adiponectin levels are elevated and positively predict progression of disease. In addition, increased levels of serum adiponectin of hemodialysis patients were associated with decrease in bone mineral density in hemodialysis patients. Thus, depending on type of renal failure should be adjusted the adiponectin levels in patients. In CKD patients without diabetic, decreasing adiponectin levels by angiotensin II receptor blockers (ARBs) may be appropriate for inhibition of disease progression.
Authors' contribution PN and MH reviewed the literatures and wrote the manu-script. HN edited the paper.

Conflicts of interest
The authors declared no competing interests.

Ethical considerations
Ethical issues (including plagiarism, misconduct, data fabrication, falsification, double publication or submission, redundancy) have been completely observed by the authors.

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